title: MICE models: superior to the HERG model in predicting Torsade de Pointes.
abstract: Drug-induced block of the cardiac hERG (human Ether-à-go-go-Related Gene) potassium channel delays cardiac repolarization and increases the risk of Torsade de Pointes (TdP), a potentially lethal arrhythmia. A positive hERG assay has been embraced by regulators as a non-clinical predictor of TdP despite a discordance of about 30%. To test whether assaying concomitant block of multiple ion channels (Multiple Ion Channel Effects or MICE) improves predictivity we measured the concentration-responses of hERG, Nav1.5 and Cav1.2 currents for 32 torsadogenic and 23 non-torsadogenic drugs from multiple classes. We used automated gigaseal patch clamp instruments to provide higher throughput along with accuracy and reproducibility. Logistic regression models using the MICE assay showed a significant reduction in false positives (Type 1 errors) and false negatives (Type 2 errors) when compared to the hERG assay. The best MICE model only required a comparison of the blocking potencies between hERG and Cav1.2.
authors.affiliation: ChanTest Corporation, 14656 Neo Parkway, Cleveland, OH 44128, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kramer
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Obejero-Paz
authors.forename: Glenn
authors.initials: G
authors.lastname: Myatt
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Kuryshev
authors.forename: Andrew
authors.initials: A
authors.lastname: Bruening-Wright
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Verducci
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Brown
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology*; D006801:Humans; D008962:Models, Theoretical; D018408:Patch-Clamp Techniques; D011237:Predictive Value of Tests; D016171:Torsades de Pointes / Q000175:diagnosis / Q000503:physiopathology*
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human